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Monday, November 10, 2008

Dr. Timothy J. Gardner, president of the American Heart Association, said some recent statin trials “have been either negative or in some ways concerning in terms of complications.” But, he added, “this one is pretty clearly a winner for statin therapy.”

A large new study suggests that millions more people could benefit from taking the cholesterol-lowering drugs known as statins, even if they have low cholesterol, because the drugs can significantly lower their risk of heart attacks, strokes and death.

The study, involving nearly 18,000 people worldwide, tested statin treatment in men 50 and older and in women 60 and older who did not have high cholesterol or histories of heart disease. What they did have was high levels of a protein called high-sensitivity C-reactive protein, or CRP, which indicates inflammation in the body.

The study, presented Sunday at an American Heart Association convention in New Orleans and published online in The New England Journal of Medicine, found that the risk of heart attack was more than cut in half for people who took statins.

Those people were also almost 50 percent less likely to suffer a stroke or need angioplasty or bypass surgery, and they were 20 percent less likely to die during the study. The statin was considered so beneficial that an independent safety monitoring board stopped what was supposed to be a five-year trial last March after less than two years.

Scientists said the research could provide clues on how to address a long-confounding statistic: that half of heart attacks and strokes occur in people without high cholesterol.

“These are findings that are really going to impact the practice of cardiology in the country,” said Dr. Elizabeth G. Nabel, director of the National Heart, Lung and Blood Institute, which was not involved in the research. “It’s at a minimum an extremely important study and has the potential to be a landmark study.”

The study is stirring debate over who should take a blood test to check CRP and under what circumstances someone with high levels of the protein should be given a statin. Because heart disease is a complex illness affected by many risk factors — including smoking, hypertension and being overweight — most researchers said high CRP alone should not justify prescribing statins to people who have never had heart problems.

Some experts cautioned against testing people for the protein unless they had other risk factors, and they said more research was needed to pinpoint the patients for whom the benefit of statins outweighs the risks. On rare occasions, statins have been linked to muscle deterioration or kidney problems, and some patients reported fogginess of memory. Other researchers recommended testing for CRP more frequently and using statins more aggressively.

The study, called Jupiter, is also fueling a debate among scientists about the protein’s importance and inflammation’s role in heart disease.

Dr. Nabel said national panels were likely to revise their official guidelines for doctors to recommend CRP testing and statin therapy for some people not previously considered candidates.

Current practice, she said, is to treat people with high cholesterol with statins and to counsel people at low risk for heart disease about diet and exercise.

“What cardiologists have never known what to do about is the intermediate range” of patients, Dr. Nabel said, who may be overweight, smoke or have hypertension but do not have the most serious red flags of high cholesterol or diabetes. “I think CRP will emerge as a new risk factor added to traditional risk factors.”

The leader of the Jupiter study, Dr. Paul M. Ridker, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital in Boston, said expanding statin use could prevent about 250,000 heart attacks, strokes, vascular procedures or cardiac deaths over five years.

Some experts not involved in the study said several million more Americans should probably be taking statins. About 16 million to 20 million do now.

“The Jupiter trial very convincingly used CRP as a way to identify another group of high-risk individuals who would not otherwise have been treated and supports the concept that those people should be treated with a statin,” said Dr. Daniel J. Rader, a heart researcher at the University of Pennsylvania School of Medicine who was not connected to the study.

Some consumer advocates and doctors raised concerns about the expense of putting relatively healthy patients on statins, which would cost the health system billions of dollars. Name-brand statins can cost $3 a day, but generics are much cheaper. Dr. Ridker said he believed that the widening use of the drugs might prevent costs associated with heart attacks and surgery.

Several experts said that although the research was significant and would affect clinical practice, the study as published did not give enough detail about which patients should now be tested for CRP or given statins.

In an accompanying editorial, Dr. Mark A. Hlatky, a professor of health research at Stanford University, questioned the cost of expanding statin use. He also said that the study, which tested people with levels of the protein over two milligrams per liter, did not indicate whether that level or a higher CRP level should be the threshold for treatment.

Dr. Sidney Wolfe, director of the health research group for Public Citizen, a nonprofit consumer advocacy group, said the study did not give enough detail about the effect of statins on participants who had only high protein levels, compared with those who also smoked or had a condition called metabolic syndrome.

Some experts questioned whether stopping the trial early had limited the possibility of some more meaningful data. Dr. Ridker said it had not.

He said the published study, as well as unpublished data, indicated that all the statin-takers experienced the same benefit, including those considered “very low risk” because they had no risk factors other than high levels of the protein.

The trial was one of the few to test statins that included many women, Hispanics and blacks, groups that all showed similar benefit from statins.

Like many clinical trials, the Jupiter study was sponsored by a pharmaceutical company, in this case AstraZeneca. It makes the drug in the trial, rosuvastatin, which is sold as Crestor. The most potent statin on the market, Crestor has been criticized by consumer health advocates who say it is more likely to lead to muscle deterioration and kidney problems.

In 2005, the Food and Drug Administration rejected a petition by Public Citizen to ban Crestor, saying its risks were not substantially different from similar drugs.

In the Jupiter study, in which people got either rosuvastatin or a placebo, there was no increase in muscle or kidney problems for those taking the statin. There was a small increase in diabetes.

Dr. Ridker, a co-inventor of a CRP test, said he first sought federal financing for the study and was turned down. He and the other scientists interviewed for this article, except for Dr. Nabel, Dr. Gardner and Dr. Wolfe, have consulted for or received research money from stain makers.

Although Crestor, which has 9 percent of the American cholesterol-lowering market, was used in this study, several experts said it seemed likely that the effect would be the same for other statins in appropriate doses, including generics.

Lisa Nanfra, executive director of commercial operations for AstraZeneca, said the company believed that there was a “unique profile of Crestor” and that the drug was “the most effective statin at lowering” bad cholesterol. The company plans to use results from the Jupiter study to seek F.D.A. approval to widen its claim about Crestor’s effectiveness.

The role of the protein and inflammation in heart disease is hotly debated. Dr. Ridker believes inflammation plays an important role, probably by causing plaque in the arteries to rupture. “Screening for cholesterol alone is like having two passengers in a car but only one air bag,” he said. “If we’re not screening for CRP, we don’t have the opportunity to save that person’s life.”

Others say cholesterol is much more important. Dr. Scott Grundy, a heart expert at the University of Texas Southwestern Medical Center, pointed out that in the Jupiter study, the statin not only lowered the protein but also significantly cut already low cholesterol levels, raising questions about whether the benefit actually came from giving patients superlow cholesterol. And because CRP can rise with short-term infections unrelated to chronic inflammation, some experts said test results needed to be weighed against other aspects of the patient’s health.

“CRP is not a standard test that everyone should have,” Dr. Rader said. “It is an additional test that you should do if you’re on the fence.”

Dr. Andrew M. Tonkin, head of cardiovascular research at Monash University in Melbourne, Australia, said though the results for those who took the statin were “strikingly positive,” given that the people in the study were relatively healthy, there needed to be a cost-benefit analysis to decide: “Are there people in whom the potential gains, although significant, are not so great as to warrant taking statins?”